Excessive daytime sleepiness (EDS) is a major public health concern in part because individuals suffering from EDS often are not productive at work, are more susceptible to accidents and generally are unable to function normally during the day. EDS is 1 of the major manifestations of individuals suffering from obstructive sleep apnea (OSA) and is frequently reported by obese individuals without sleep apnea. The mechanisms underlying EDS are not clear. We have demonstrated that the pro-inflammatory and fatigue-inducing cytokines, tumor necrosis factor-a (TNFa) and interleukin-6 (IL-6) are elevated in conditions of pathological sleepiness, e.g., sleep apnea, or in experimentally-induced sleepiness, e.g., following total sleep deprivation. Further work funded by the initial grant (HL-64415) demonstrated that (1) even mild sleep restriction to 6 hours per night for 1 week is associated with increased sleepiness, decreased performance, and increased levels of TNFa and IL-6, and (2) hypercytokinemia and its associated insulin resistance in obese OSA patients is not reversed by the most common treatment for this disorder, i.e., continuous positive airway pressure (CPAP). Additionally, neutralizing TNFa in obese apneics reduces EDS markedly and significantly. In this application, we propose to study the effects of recovery sleep, obesity, and middle-age on sleepiness, performance, and inflammatory cytokines after one week of sleep restriction in normal sleepers (specific aims 1-3). We hypothesize that recovery sleep for 2 nights does not adequately reverse the adverse effects of mild sleep restriction, whereas obesity and middle-age augment the adverse effects of mild sleep restriction. Furthermore, we propose to test (a) 24-hour circadian pattern of cytokines and adipokines (leptin and adiponectin), and insulin resistance/visceral fat in nonobese apneics, and in weight, age, and gender matched controls; and (b) the effects of CPAP use in a cross-over placebo controlled design (specific aim 4). We hypothesize that symptomatic nonobese apneics exhibit higher levels of IL-6, TNFa, and insulin resistance/visceral fat compared to controls and that CPAP compared to sham CPAP has a mild but significant effect on the immune/metabolic aberrations. In these studies, we will use a series of experimental techniques including nighttime polysomnography, MSLT, PVT, actigraphy, 24-hour blood sampling, and assays for cortisol, TNFa, IL-6, leptin, adiponectin, and abdominal computerized tomography (CT) for body fat distribution, CPAP, and Sham CPAP. These studies collectively will provide additional evidence for a role of TNFa and IL-6 in EDS and OSA and lay the foundation for the development of novel therapeutic interventions.